There is an urgent need for new anti-HIV-1 therapies that block non-enzymatic stages of the viral replicative cycle, such as viral entry. For entry, HIV-l must interact with both CD4 and a fusion coreceptor such as CCR5 on the target cell surface. Since CCR5 is critical for HIV-1 transmission and pathogenesis, soluble forms of CCR5 are attractive candidates for therapy. We recently discovered that synthetic CCR5 peptides possess anti-HIV- 1 activity that is dependent upon sulfation of key tyrosine residues. This Phase I project seeks to develop CCR5-based sulfopeptides as antiviral agents. Using the atomic-level structures of gpl2O, a series of linear and nonlinear CCR5 sulfopeptides will be synthesized and evaluated for activity. The most promising peptides will undergo a detailed evaluation of their specificity, potency, and breadth of antiviral activity as well as their effects on CCR5 function. During the Phase II project, the peptides will be optimized for pharmacology, tolerability and antiviral activity in vivo. The optimal drug candidate will be produced using current Good Manufacturing Practices for clinical testing in HIV-infected individuals. This project seeks to develop a novel class of antiretroviral agents using advanced technologies in the areas of peptide chemistry, compound screening, and virology. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE